title: Structure-activity relationships and identification of optmized CC-chemokine receptor CCR1, 5, and 8 metal-ion chelators.
abstract: Chemokine receptors are involved in trafficking of leukocytes and represent targets for autoimmune conditions, inflammatory diseases, viral infections, and cancer. We recently published CCR1, CCR8, and CCR5 agonists and positive modulators based on a three metal-ion chelator series: 2,2'-bipyridine, 1,10-phenanthroline, and 2,2';6',2″-terpyridine. Here, we have performed an in-depth structure-activity relationship study and tested eight new optimized analogs. Using density functional theory calculations we demonstrate that the chelator zinc affinities depend on how electron-donating and -withdrawing substituents modulate the partial charges of chelating nitrogens. The zinc affinity was found to constitute the major factor for receptor potency, although the activity of some chelators deviate suggesting favorable or unfavorable interactions. Hydrophobic and halogen substituents are generally better accommodated in the receptors than polar groups. The new analog brominated terpyridine (29) resulted in the highest chelator potencies observed so far CCR1 (EC50: 0.49 μM) and CCR8 (EC50: 0.28 μM). Furthermore, we identified the first selective CCR5 agonist chelator, meta dithiomethylated bipyridine (23). The structure-activity relationships contribute to small-molecule drug development, and the novel chelators constitute valuable tools for studies of structural mechanisms for chemokine receptor activation.
authors.affiliation: Department of Drug Design and Pharmacology, ‡Department of Neuroscience and Pharmacology and ⊥The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen , DK-1165 Copenhagen, Denmark.
authors.forename: Alexander
authors.initials: A
authors.lastname: Chalikiopoulos
authors.forename: Stefanie
authors.initials: S
authors.lastname: Thiele
authors.forename: Mikkel
authors.initials: M
authors.lastname: Malmgaard-Clausen
authors.forename: Patrik
authors.initials: P
authors.lastname: Rydberg
authors.forename: Vignir
authors.initials: V
authors.lastname: Isberg
authors.forename: Trond
authors.initials: T
authors.lastname: Ulven
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Frimurer
authors.forename: Mette M
authors.initials: MM
authors.lastname: Rosenkilde
authors.forename: David E
authors.initials: DE
authors.lastname: Gloriam
mesh_terms: D015082:2,2'-Dipyridyl / Q000031:analogs & derivatives* / Q000737:chemistry; D000818:Animals; D065100:CCR5 Receptor Antagonists; D019556:COS Cells; D002614:Chelating Agents / Q000737:chemistry*; D002522:Chlorocebus aethiops; D015870:Gene Expression; D054879:Halogenation; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D008024:Ligands; D010618:Phenanthrolines / Q000737:chemistry*; D011725:Pyridines / Q000737:chemistry*; D054389:Receptors, CCR1 / Q000819:agonists / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000235:genetics; D019713:Receptors, CCR5 / Q000819:agonists / Q000737:chemistry* / Q000235:genetics; D054401:Receptors, CCR8 / Q000819:agonists / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000235:genetics; D013329:Structure-Activity Relationship; D015032:Zinc / Q000737:chemistry*
chemical_list: C517923:(2,2'-6',2'')-terpyridine; C515300:CCR1 protein, human; D065100:CCR5 Receptor Antagonists; C584933:CCR5 protein, human; C103330:CCR8 protein, human; D002614:Chelating Agents; D008024:Ligands; D010618:Phenanthrolines; D011725:Pyridines; D054389:Receptors, CCR1; D019713:Receptors, CCR5; D054401:Receptors, CCR8; D015082:2,2'-Dipyridyl; D015032:Zinc; C025205:1,10-phenanthroline